1. Field of the Invention
The present invention relates generally to the field of pharmacology and medicine. More particularly, it concerns hydrophilic polymer conjugated antibacterial agents, such as pegylated aminoglycosides for the treatment of infections such as, e.g., biofilm infections.
2. Description of Related Art
Biofilms are protective coats produced by bacterial communities that can allow bacteria to become resistant to treatment and can present very problematic and sometimes life-threatening chronic infections. The clinical treatment of biofilm infections often proves to be particularly problematic because they are difficult to treat and generally display a reduced sensitivity to regular antibiotics, e.g., resulting from protection from and encasement in the biofilm matrix.
Biofilm infections, such as pneumonia in cystic fibrosis patients, chronic wounds, chronic otitis media and implant- and catheter-associated infections, affect millions of people in the developed world each year and many deaths occur as a consequence. One of the important hallmarks of chronic biofilm-based infections is extreme resistance to antibiotics and many other conventional antimicrobial agents.
An example of a disease commonly associated with biofilm infections is cystic fibrosis. Cystic fibrosis (CF) is an inherited autosomal recessive disease that is commonly diagnosed at early childhood and can result in chronic infections (Ratjen and Doring, 2003). Prevalence varies among different ethnic populations (Dodge et al., 2007) and affects about 30,000 children and adults in the United States (70,000 worldwide) according to the Cystic Fibrosis Foundation. A defective cystic fibrosis transmembrane regulator (CFTR) causes faulty transport of sodium chloride in many pars of the body, including the lungs, intestine, pancreas and liver (Dodge et al., 2007), leading to thick and viscous mucus secretion. Over 1500 mutations in the chromosome 7 which codes for CFTR have been identified indicating the diversity of the disease and can present difficulties in management (Ratjen, 2009). As a result of thick and viscous mucous secretions, patients with CF are prone to repeated infections of Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae (Dodge et al., 2007; Gilligan, 1991).
P. aeruginosa starts colonizing in the airway as a non-mucoid strain. As the infection progresses, the bacterium switch to a mucoid form and secrete excessive amount of extracellular matrix forming biofilm ultimately (George et al., 2009; Wagner and Iglewski, 2008; Ramsey and Wozniak, 2005). Biofilm, a self-produced matrix, consists of polysaccharides, proteins, and DNA (Flemming and Wingender, 2010). The formation of biofilm imposes a higher antibiotic resistance to P. aeruginosa in CF patients which can be up to 1000 times of the planktonic phase of P. aeruginosa (Aaron, 2007; Fux et al., 2005). The factors from biofilm that contributes antibiotic resistance includes: slow growth rates, low antibiotic penetration, internal hypoxic environment within the microcolonies, high cell density (up to 109 CFU/mL), excessive extracellular matrices, pH alterations, altered nutrient requirements (Ramsey et al., 1999). Hence the development of better treatments for biofilm related infections is a major focus in CF therapeutics investigations (Pier, 2012; Høiby, 2011).
Recently, FDA approved tobramycin inhalation powder for use in CF patients with P. aeruginosa. Despite clinical benefits of inhaled tobramycin, biofilm infections remain resistant against this drug (Strateva and Yordanov, 2009; Zhang and Mah, 2008; MacLeod et al., 2000). There is an urgent need to improve the efficacy of antibiotics. Antimicrobial agents are currently used as first line agents in infections yet typically have poor activity against the chronic biofilm infections. Clearly, there exists a need for improved compounds for treating biofilm infections.